Selective action of drugs is an important prerequisite for their successful application in treating or preventing disease. However, because of the many similarities (e.g. in membrane structure and function, metabolic properties, etc.) which exist between the cells to be treated with the drug and normal cells, a specific effect is more often than not the exception rather than the rule. Consequently, side effects occur which hamper or even prevent treatment of a wide variety of diseases ranging from cancer to inherited metabolic disorders. A problem additional to that of poor drug selectivity, is the inability of certain drugs to reach diseased areas. For example, in many parasitic diseases, drugs cannot kill intracellular micro-organisms because of the protection offered to the parasites by cellular membranes in the form of permeability barriers to the drugs. Alternatively, drugs cannot reach the target mainly because of their large size. This is the case with enzymes which are potentially useful in the treatment of some enzyme deficiences affecting the central nervous system but are unable to cross the blood-brain barrier.
The use of carriers for the transport of drugs to target areas is now recognized as a promising method of improving drug selectivity and action. Many types of carriers such as macromolecular cells, viruses and synthetic particles have been proposed.
It is, however, apparent that most known carriers are limited in the range and quantity of drugs which they can accommodate and also in their ability to prevent contact of their drug moiety with the normal biological environment or to promote its access to areas in need of treatment. In addition, there are difficulties related to the toxicity of the carrier's components, to their availability or cost and to the preparation of the carrier-drug unit. Consequently, extensive efforts have been made, especially in the last decade, towards the development of an ideal drug carrier. Such a carrier should be capable of delivering a wide variety of agents into the precise site of action within the biological entity with no untoward effects on the (normal) remainder of the entity.
The utility of any carrier system is determined by: (1) lack of cytoxicity, (2) biodegradability, (3) lack of immunogenicity (unless designed to specifically carry antigens), (4) the efficiency with which molecules and macromolecules are incorporated into the carrier under conditions that do not alter and/or inactivate the incorporated materials, (5) the ability to protect carrier-associated materials from alteration and/or breakdown by exposure to extracellular environment, and (6) the efficiency with which carrier-associated materials are transferred to cells.
The use of lipid vesicles (liposomes) for the delivery of drugs for both in vivo and in vitro studies is now in wide use since they consist of biodegradable lipid components in a spontaneously forming bilayer configuration, the composition of which can be varied to a marked extent. This variability allows the physical and chemical properties of liposomes to be altered and this can be exploited to alter their retention and uptake in vivo. Thus, the fixed charges on the liposome surface can be varied by incorporating long-chain, charged amphipaths such as fatty acids or naturally occurring negatively charged phospholipids.
Two important potential uses of such carrier-entrapped drugs in vivo are: (1) they could be used as a means for controlled release of small quantities of drugs over long periods of time, possibly also associated with decreased metabolic breakdown of the trapped drug, and (2) they could function to direct drugs to particular tissues.
Since many cancers are resistant to chemotherapy, it would be of great importance if a carrier could be devised as a means of increasing the effectiveness of anticancer drugs by exploiting one or the other of the properties mentioned above. This would be a clear advantage to the carrier-entrapped drugs since the pharmacokinetics of the drug need not be altered by chemically modifying the drug, which may in turn modify its biological effect, but by altering the composition of the drug carrier.